Since 1922, insulin has been the only available therapy for the treatment of type diabetes and other conditions related to lack of or diminished production of insulin. Despite decades of research and the advent of pancreatic islet cell transplantation in 1974 and newer claims of success resulting from the Edmonton Protocol for islet cell transplantation, the success has not been replicated in the United States. At four years post-transplant, fewer than 10% of patients who have received islet cell transplants remain insulin independent. Additionally, despite new immune suppression protocols, there is an 18% rate per patient of serious side effects.
Over the past several decades, there have been several newly identified peptide sequences involved in glucose metabolism, some of which are believed to be the most potent islet stimulating hormones. These hormones include peptide sequences of Glucagon Like Peptide-1 (GLP-1) and its analogs, Gastric Inhibitory Peptide/Glucose-Dependent Insulinoptropic polypeptide (GIP), Amylin, and its analog, Pramlintide, and homologous compounds to GLP-1, such as Liraglutide (NN2211) and Exendin-4, Islet Neogenesis Associated Peptide (INGAP), the biologically active hamster INGAP peptides, other nonhuman mammalian INGAP analogs, the Human proIslet Peptide and biologically active peptides having significant homology to the Human ProIslet Peptide, and biologically active derivatives of the Human proIslet Peptide and hamster INGAP peptide, which derivatives can include amino acid additions and/or substitutions in the Human proIslet Peptide and hamster INGAP peptide, and/or compounds that block the degradation of Human proIslet Peptide, hamster INGAP, GLP-1, GLP-1 receptor analog, such as Exendin-4 or Liraglutide, or GLP-1 analogs, or compounds which halt the destruction of GLP-1, such as Dipeptidyl Peptidase-4 Inhibitors, which may have the potential to regenerate pancreatic islet cells that produce insulin and other stimulators of islet regeneration and include but are not limited to Vilidagliptin, Sidagliptin, Saxagliptin and PHX1149. Other agents which also have the potential to expand islet cell mass include gastrin and epidermal growth factor-1. Proof of the elasticity of the pancreas with respect to the generation of new pancreatic cells throughout one's lifetime accompanied by pancreatic cell death or apoptosis has replaced the long held concept that the number of insulin producing islet cells is fixed at birth and sustained throughout life. It is currently well accepted that pancreatic islet cell neogenesis occurs from preexisting islet cells and through transformation from exocrine ductal cells. Data demonstrates that, even decades after the onset of 1 diabetes, insulin producing islet cells can be regenerated. For example, patients with type 1 diabetes who can make normal levels of c-peptide during pregnancy and patients who have been on long term immunosuppression for kidney transplantation have been observed to regenerate insulin producing islet cells.
Additionally, over the past decade, clinical trials have been conducted to evaluate the impact of a number of immune modulators that may arrest the destruction of the pancreas. The studies and types of agents to potentially arrest the destruction of islet cells have varied considerably. The types of agents include general immunosuppressant agents which have typically been used in organ transplants, specifically targeted antibodies to those lympocytes which attack the islets, along with other agents such as Vitamin D, in which a deficiency has been associated with an higher incidence of diabetes.
Anti CD-3 antibodies that target the immune response and specifically block the T-lymphocytes that cause islet cell death in type 1 diabetes have been utilized as well as heat-shock proteins to arrest the destruction of insulin-producing cells and anti-GAD65 antibody vaccines. Trials are underway with a number of diverse agents or combination of agents among newly diagnosed patients with diabetes. Currently the immune agents Mycophenolate mofetil and Daclizumab, which have been used to suppress rejection among organ transplants patients is being studied for usage in newly diagnosed type 1 diabetes patients. Rituximab, an anti CD20 agent, which is an FDA approved agent for the treatment of B-lymphocyte lymphoma, is also being studied in the preservation of islet cells among newly diagnosed diabetes patients. Early trials have shown promising results and ongoing trials are underway in newly type 1 diabetes patients using the anti CD3 antibody, hOKT3 gamma1 (Ala-Ala) and the monoclonal antibody TRX4 (ChAglyCD3).
DiaPep277 is another immune agent directed at the onset of type 1 diabetes to halt the destruction of islets. DiaPep277 is a heat shock protein 50 which is believed to impact the Th1 cells which release cytokines and pro-inflammatory cells which destroy islet cells, is being studied in adults and children with newly diagnosed patients with diabetes and also in patients with Latent Autoimmune Diabetes in Adults (LADA).
The aim of all of the therapies that are proposed to prevent further immune destruction of the islet cells, does not enhance further replication of new islet cells, which is a very slow process. Typically, a healthy individual requires about 1.5 million islet cells to maintain glucose homeostatsis. At the time of diagnosis, both type 1 and type 2 patients only retain about 50% of their typical islet cell mass. This ongoing destructive process in type 1 diabetes is typically more rapid and progressive than in type 2 diabetes leading to multiple daily insulin injections to survive. The typical healthy adult has a usual cell death rate for islets of between 1000 and 2000 cells per day; the human islet lifespan being about 3 years. Each day, the same number of new islets are formed from precursor cells within the pancreas, both in the endocrine and exocrine portions of the organ. Thus, even if immune-halting agents to prevent further islet loss, because the daily regeneration rate of new islet production is only about 0.1% per day, it could take years to repopulate the pancreas with insulin producing without such an immune-blocking compound being combined with a regeneration compound such as Human proIslet Peptide, a DPP-4 inhibitor, and GLP-1 agonist, or GLP-1 receptor agonist.
To date, however, there has been no single or combination therapy that has been successfully used to treat the underlying disease mechanisms of type 1 diabetes or conditions in which there is a lack of or diminished insulin production. There remains a need for new methods and pharmaceutical compositions for treating type 1 diabetes mellitus. Especially needed are methods and compositions that can also treat the many other conditions in which the lack of or diminished insulin production has a causative role or contributes to the symptoms of patients in need of treatment. At present, there appears to be no treatment that ameliorates the symptoms of type 1 diabetes by targeting the underlying disease mechanism. The present invention meets the need for improved therapies for treating type 1 diabetes and other conditions.